Author + information
- Received January 18, 2005
- Revision received March 3, 2005
- Accepted March 10, 2005
- Published online July 5, 2005.
- Ron T. van Domburg, PhD⁎,⁎ (, )
- Karel Sonnenschein, MSc⁎,
- Robby Nieuwlaat, MSc†,
- Otto Kamp, MD, PhD‡,
- Corstiaan J. Storm, MD§,
- Jeroen J. Bax, MD, PhD∥ and
- Maarten L. Simoons, MD, PhD⁎
- ↵⁎Reprint requests and correspondence:
Dr. Ron T. van Domburg, Erasmus Medical Center, Thoraxcentrum, Ba 559, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
Objectives The goal of this research was to clarify whether the benefit of reperfusion therapy for myocardial infarction was sustained long-term and to assess the gain in life expectancy by reperfusion therapy.
Background Reperfusion therapy in acute myocardial infarction reduces infarct size and increases hospital survival.
Methods We analyzed the 20-year outcome of 533 patients (mean age 56 years; 82% men) who were randomized to either reperfusion therapy or conventional therapy during the years 1981 to 1985.
Results Mean follow-up was 21 years (range 19 to 23 years). At follow-up, 101 patients (36%) of the 269 patients allocated to reperfusion treatment and only 71 patients (26%) of the 264 conventionally treated patients were alive (p = 0.02). The cumulative 10-, 15-, and 20-year survival rates were 69%, 48%, and 37% after reperfusion therapy and 59%, 38%, and 27% in the control group, respectively (p = 0.005). Life expectancy of the reperfusion group was 15.2 years versus 12.4 years in the conventionally treated group (p < 0.0001). Myocardial re-infarction and subsequent coronary interventions were more frequent after reperfusion therapy, particularly during the first year. In multivariable analysis, reperfusion therapy was an important independent predictor of lower mortality at long-term follow-up (hazard ratio 0.7; 95% confidence interval 0.6 to 0.8). Other independent predictors of mortality were age, impaired left ventricular function, multivessel disease, infarct size, and inability to perform an exercise test at the time of discharge.
Conclusions This is the first study demonstrating sustained (20-year) improved survival after reperfusion therapy. The gain in life expectancy was almost three years, representing about one-third of the life-years lost by myocardial infarction.
Reperfusion therapy in acute myocardial infarction (MI) reduces infarct size, preserves left ventricular function, and, hence, increases hospital survival by rapid restoration of coronary flow distal to the culprit lesion (1–3). This survival benefit is maintained during the first decade (4–7). However, in order to assess the gain in life expectancy by reperfusion therapy, longer follow-up is necessary. Therefore, we conducted a 20-year follow-up of patients participating in the study of reperfusion therapy by the Interuniversity Cardiology Institute of the Netherlands (ICIN) (1981 to 1985) (1). The aim of this 20-year follow-up study was to investigate whether the benefit of early reperfusion therapy was sustained in the second decade and to assess the gain in life expectancy by reperfusion therapy (4,8).
From 1981 to 1985, 533 patients in five participating hospitals were randomized to either immediate reperfusion therapy (n = 269) or conventional treatment (n = 264). The study design and initial results have been previously reported (1). Acute coronary angiography was performed in 233 of 269 patients allocated to reperfusion therapy. If the infarct-related coronary artery appeared to be occluded, streptokinase (250,000 U) was administered intracoronary. In the last 117 patients, intracoronary administration was preceded by intravenous streptokinase (500,000 U). In 46 patients with severe residual stenosis of the infarct-related coronary artery, coronary angioplasty was attempted as part of the re-canalization procedure (1,9,10).
Follow-up vital status was obtained by reviewing the hospital records and from general practitioners and civil registries. Data were collected on death, recurrent MI, and coronary revascularization procedures. The diagnosis of recurrent MI was based on the opinion of the treating physician and verified from hospital discharge letters, when available. If necessary, patients were contacted by telephone. Follow-up was complete in 99%. Survival status of four patients (two patients allocated to reperfusion therapy and two allocated to conventional treatment) who had moved abroad could not be retrieved, and the last available follow-up data were used.
Continuous variables were compared by Student ttest and categorical variables by chi-square tests. Cumulative survival analyses were constructed using the Kaplan-Meier method. Among patient subgroups, the Mantel and Haenszel log-rank test was used to compare survival and event-free survival curves.
The expected survival in a reference population was calculated using age- and gender-specific mortality data from the Netherlands in 1983, and compared with survival in patients after MI. Because the mean age of our infarct study population was 56 years and 80% were male, mortality risks were weighted accordingly.
The Cox proportional hazards model was used to identify independent risk factors for 20-year mortality. Preselected patient baseline characteristics were: age, gender, previous MI, infarct site, Killip class at admission, time from onset to treatment allocation, and sum of ST-segment elevation at admission. In the analyses, the following data were also collected in-hospital: atrial fibrillation and ventricular fibrillation/flutter, infarct size as assessed from cardiac enzyme release, the (in)ability to perform an exercise test before discharge, extent and severity of coronary artery disease, and left ventricular function. Myocardial reinfarction may change a patient’s prognosis, therefore, a time-dependent Cox proportional hazards model was used to investigate the effect of myocardial reinfarction during follow-up on subsequent mortality using BMDP statistical software (University of California, Berkeley, California).
Life expectancy after MI, with or without reperfusion therapy, was calculated from the area under the Kaplan-Meier curves truncated at 20 years (11). To calculate the exact life expectancy, the curves were extended beyond 20 years using the age- and gender-specific mortality data from the reference population in the Netherlands, assuming that those post-MI patients who had survived 20 years would have similar further life expectancy as their age- and gender-matched peers. The yearly mortality rate of a 76-year-old male in the Netherlands is around 4%.
Patients were randomized to receive either reperfusion therapy (n = 269) or conventional treatment (n = 264). The mean age at enrollment was 56 years (range 28 to 71 years), 82% were men, 22% had previous infarction, and 46% were admitted with an anterior infarction (Table 1).
The 30-day mortality was 6.5% after reperfusion therapy and 11.8% after conventional treatment (Table 1). During a median follow-up of 21 years (range 19 to 23 years), 361 patients (69%) died, 168 patients allocated to reperfusion therapy (64%) and 193 controls (74%). The cumulative 10-, 15-, and 20-year survival rates were 69%, 48%, and 37% in patients treated with reperfusion therapy and 59%, 38%, and 27% in the conventional group, respectively (Fig. 1).After one year, the two curves were approximately parallel. Thus, the 10% early (one-year) survival benefit by reperfusion therapy was sustained throughout 20 years (log-rank test, p = 0.005). The corresponding expected survival of the age- and gender-specific reference population after 10, 15, and 20 years was 86%, 73%, and 56% (Fig. 1). In the patients with successful reperfusion therapy (80%), the cumulative 10-, 15-, and 20-year survival rates were 78%, 55%, and 45%, respectively. This was significantly higher than in the total reperfusion group (p < 0.05).
Cumulative 20-year survival
Overall, there was an absolute benefit of 105 lives saved per 1,000 treated patients (95% confidence interval [CI] 25 to 185). This benefit was apparent in all subgroups (Table 2).Larger benefit was observed in younger patients when compared with elderly (>60 years), in patients with anterior MI, and in patients treated within 2 h after the onset of symptoms.
Life expectancy was 12.4 years after conventional therapy and was increased by reperfusion therapy to 15.2 years, a difference of 2.8 years (Table 2). The beneficial effect of reperfusion therapy as compared with conventional treatment was apparent in all subgroups studied. In patients with extensive ST-segment elevation, there was a beneficial effect of 3.9 years by reperfusion therapy. Patients with an anterior infarct had a gain of 3.4 life-years compared with 2.5 years after inferior infarction. In patients with early treatment (<2 h onset complaints), the gain in life expectancy was 3.6 years. The greatest benefit was achieved in the subgroup of patients with extensive (ST-segment elevation ≥1.2 mV) anterior infarction, treated within 2 h of symptom onset. In these patients life expectancy was only 9.0 years with conventional therapy, increasing by 4.9 years to 13.9 years with reperfusion therapy.
We compared these results with our earlier reported life expectancy model based on one-year outcome (Table 3)(8). Overall, the earlier model underestimated the beneficial effect of reperfusion therapy by a factor of two. Instead of an estimated gain of 1.5 life-years, we observed a 2.8-life-years benefit after reperfusion therapy. In the reference population, in the 1980s, the expected survival was 21.1 years. In those patients suffering from MI, 8.7 years of these 21.1 life-years were lost when treated conventionally. About one-third of this loss (2.8 years) could be restored by timely reperfusion therapy.
Re-infarction and revascularization
An excess of re-infarction was observed during the first four years after reperfusion therapy (Fig. 2A).The rate of re-infarction was particularly high in the first year: 14.5% and 5.9% in the reperfused and control patients, respectively. In years 2 to 4, the annual re-infarction rate averaged about 3.0% after reperfusion therapy and 1.5% in controls, dropping to 1.2% in years 6 to 10, and below 0.5% from year 11 onward in both treatment groups. After conventional treatment, the same coronary artery was involved in 44% of the re-infarctions and in 64% after reperfusion therapy.
Coronary revascularization in addition to immediate reperfusion therapy during hospitalization was not common. Only 7 patients underwent revascularization (all percutaneous coronary intervention [PCI]) in the reperfusion group and 10 patients in the conventional group. After discharge, coronary revascularization procedures were performed predominantly in the first year after the index infarct, somewhat more frequently in the reperfusion group (reperfusion: 20.4%, conventional: 17.0%) (Fig. 2B). After the first year, revascularization was infrequent and not significantly different among the treatment groups (reperfusion: 1.0%/year; conventional: 0.7%/year). Of 46 patients in whom elective coronary angioplasty was performed as part of the initial reperfusion process, 39% underwent repeat revascularization (7 PCI and 13 coronary artery bypass grafting). This was similar to those reperfused patients without acute PCI. Event-free survival, without recurrent infarction or revascularization was similar in both treatment groups: 46% at 5 years, 32% at 10 years, and 14% after 20 years.
Univariable and multivariable predictors of mortality
Predictors of 20-year mortality were age, a previous MI, anterior infarction, extensive ST-segment elevation, and severe heart failure or cardiogenic shock (Table 4).However, after inclusion of parameters representing reperfusion therapy and subsequent clinical course, these baseline characteristics were replaced by more precise measurements of infarct size, left ventricular function, and extent of coronary disease. Yet, adjusting for all other baseline characteristics, reperfusion therapy remained an important independent predictor of lower mortality (hazard ratio [HR] 0.7; 95% CI 0.6 to 0.8) as compared with conventional therapy (Table 4). Also, nonfatal myocardial re-infarction was a predictor of mortality using the adjusted time-dependent Cox model (HR 1.7; 95% CI 1.3 to 2.2).
This follow-up study demonstrates that the early survival benefits of reperfusion therapy are sustained for 20 years, and probably life-long. The survival benefit of reperfusion therapy was 6% at hospital discharge, 10% at one year, and remained about 10% throughout 20 years of follow-up. After 20 years, survival with conventional therapy was only 27%, which is approximately one-half of the survival in the normal reference population (56%). With reperfusion therapy (survival 37%) about one-third of this loss could be restored. These observations extend earlier reports on patients followed for a decade after reperfusion therapy or conventional therapy (4–7). Reperfusion therapy with intracoronary streptokinase (followed in some patients by rescue PCI), was a predictor of long-term survival, independent of baseline characteristics, infarct size, or cardiac function at hospital discharge. This suggests that the benefits of reperfusion therapy are not only related to limitation of infarct size and preservation of left ventricular function, but also to the infarct zone. Re-infarction, which often occurred in the same territory as the index infarct, was an important predictor of subsequent mortality using a time-dependent Cox model.
In the two decades since this early study, reperfusion therapy has evolved. It is likely that the benefits of current therapy with primary PCI and stenting will be larger than the important benefit reported by us. Indeed, successful reperfusion can now be achieved in more than the 80% of our study, while the incidence of re-infarction has also been significantly reduced.
The survival benefit after reperfusion therapy at one month was 6%, increasing to 10% at one year and beyond. No additional benefit of reperfusion therapy was observed after the first year, in spite of the better left ventricular function at hospital discharge. This may be due to the excess of re-infarction, with associated loss of ventricular function, as was observed during the first years in the reperfusion group.
We had the unique opportunity to verify the life expectancy model, which was developed on the basis of earlier infarct studies and one-year outcome (8). In that report, the extrapolated life expectancy was 15.3 years with conventional therapy and 16.8 years after early reperfusion, a gain of 18 months. After extended follow-up in the current study, we were able to calculate life expectancy more accurately and we found that life expectancy was overestimated by one to three years with the original one-year model (Table 4), but we also observed an almost two-fold greater (2.8 years) gain in life expectancy in favor of reperfusion therapy. Apparently the (necessary) assumptions in the original model with limited follow-up were not accurate. These observations indicate that estimates of life expectancy and cost-effectiveness analyses of medical interventions should be interpreted with caution as long as true long-term follow-up data are lacking. Therefore, true long-term follow-up studies of randomized trials should be conducted more frequently.
The treatment of patients with acute MI has evolved in major ways since this trial was conducted between 1981 and 1985. Intracoronary streptokinase, although apparently effective, is no longer given and has been replaced by intravenous administration of different fibrinolytic agents (streptokinase, alteplase, reteplase, tenecteplase) or, preferably, direct PCI (12,13). Nevertheless, our main finding, that reestablishment of coronary patency improves long-term survival, will remain valid. In fact, it is now to be expected that direct PCI has further improved life expectancy after reperfusion therapy, because direct PCI is associated with better reperfusion as well as lower re-infarction rates and fewer strokes than thrombolytic therapy (12). Because of limited availability of angioplasty centers worldwide, only a minority of patients with evolving MI undergo primary angioplasty (14). Therefore, at least in the near future, fibrinolytic therapy will remain an important method for reperfusion. The patients in our study were treated with aspirin or coumadin and with beta-blockers. In addition, it has been shown that systematic treatment with statins and angiotensin-converting enzyme inhibitors further reduces the incidence of mortality and re-infarction (13). Taken together, newer, more effective methods for reperfusion therapy and more effective secondary prevention may be expected to further extend the gain in life expectancy as observed in our study. The subgroup analyses in the present study may be questioned because of the lack of power. However, our data confirms the findings of other studies (15), that reperfusion therapy is beneficial in all patients with evolving MI, and particularly beneficial when administered early after symptom onset in patients with extensive (anterior) infarcts.
This long-term follow-up study demonstrates that very early aggressive reperfusion therapy improves survival after MI at least beyond the second decade. Reperfusion therapy prolongs life almost three years and restores one-third of the loss in life-years by the infarct. These findings reemphasize that all efforts should be made to identify patients with evolving MI, and to provide rapid, effective reperfusion therapy without delay.
The Interuniversity Cardiology Institute of the Netherlands funded the original study.
- Abbreviations and Acronyms
- confidence interval
- hazard ratio
- myocardial infarction
- percutaneous coronary intervention
- Received January 18, 2005.
- Revision received March 3, 2005.
- Accepted March 10, 2005.
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